U.S. patent application number 16/661352 was filed with the patent office on 2020-06-04 for non-invasive brain water monitoring device for cerebral edema and cerebral autoregulation monitoring system and method.
The applicant listed for this patent is Drexel University. Invention is credited to Baruch Ben Dor, Juan Du, Meltem Izzetoglu, Shadi Malaeb.
Application Number | 20200170554 16/661352 |
Document ID | / |
Family ID | 57147054 |
Filed Date | 2020-06-04 |
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United States Patent
Application |
20200170554 |
Kind Code |
A1 |
Izzetoglu; Meltem ; et
al. |
June 4, 2020 |
NON-INVASIVE BRAIN WATER MONITORING DEVICE FOR CEREBRAL EDEMA AND
CEREBRAL AUTOREGULATION MONITORING SYSTEM AND METHOD
Abstract
A system, device and methods for quantitatively monitoring and
evaluating changes in water and hemoglobin content in the brain in
a non-invasive manner are provided. The system may be used for
real-time detection and monitoring of brain edema and/or for an
assessment of cerebral autoregulation.
Inventors: |
Izzetoglu; Meltem; (Bryn
Mawr, PA) ; Du; Juan; (Broomall, PA) ; Ben
Dor; Baruch; (Radnor, PA) ; Malaeb; Shadi;
(Ardmore, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Drexel University |
Philadelphia |
PA |
US |
|
|
Family ID: |
57147054 |
Appl. No.: |
16/661352 |
Filed: |
October 23, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15136899 |
Apr 23, 2016 |
10499838 |
|
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16661352 |
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62152377 |
Apr 24, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/4878 20130101;
A61B 5/6814 20130101; A61B 5/6833 20130101; A61B 5/14553 20130101;
A61B 5/01 20130101; A61B 5/4064 20130101; A61B 2562/166 20130101;
A61B 5/14552 20130101; A61B 5/0075 20130101 |
International
Class: |
A61B 5/1455 20060101
A61B005/1455; A61B 5/00 20060101 A61B005/00; A61B 5/01 20060101
A61B005/01 |
Goverment Interests
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with government support under
Contract No. W81XWH-08-2-0573 awarded by the U.S. Army,
Telemedicine and Advanced Technology Research Center (TATRC). The
government has certain rights in this invention.
Claims
1. A method of assessing cerebral autoregulation in a mammalian
subject, comprising the steps of: administering to the subject
intravenously a composition comprising an aqueous solution;
obtaining multiple measurements from the subject over time of
oxygenated (oxyHb), deoxygenated hemoglobin (deoxyHb) and water
using near infrared spectroscopy (NIRS); and analyzing the multiple
measurements from the subject against a reference standard to
identify any change in the measurements of oxyHb, deoxyHb and water
characteristic of hypoxic injury or aberrent cerebral
autoregulation.
2. The method according to claim 1, further comprising the steps
of: obtaining from of the subject baseline measurements of oxyHb,
deoxyHb and water using NIRS prior to administration of said
composition; and correcting said additional measurements by
subtracting the baseline measurements prior to analysis.
3. The method according to claim 1, further comprising the step of
obtaining said measurements by use of an NIRS sensor in contact
with the tissue of the forehead of the subject wherein said NIRS
measurements are collected from right and left hemispheres of the
subject's frontal cortex simultaneously.
4. The method according to claim 1, wherein the composition
comprises a component selected from saline, an aqueous solution of
saline, an analgesic agent, Fentanyl, a paralytic agent,
vecuronium, or combinations of two or more of said components.
5. The method according to claim 1, wherein the composition
comprises one or more of a concentration of 10 ml/kg weight saline,
a concentration of 50 mcg/kg Fentanyl, and a concentration of
vecuronium of about 0.1 mg/kg.
6. The method according to claim 1, wherein the composition is
administered at a rate of infusion of between 10 to about 20
ml/minute, wherein the time of infusion is from about 1 to 2
minutes, and wherein the volume of composition infused is from
about 25 to about 40 ml.
7. The method according to claim 1, further comprising measuring
local tissue oxygen saturation.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of co-pending U.S.
application Ser. No. 15/136,899 filed on Apr. 23, 2016 which claims
the benefit under 35 USC .sctn. 119(e) of U.S. Provisional Patent
Application No. 62/152,377, filed Apr. 24, 2015.
BACKGROUND
[0003] Brain edema is the accumulation of fluid in the brain and
resultant swelling of the brain. Causes of brain edema may include
trauma, a tumor, exposure to toxic substances, and other injuries.
About 1.7 million people in an average year in the U.S. incur a
head injury requiring medical care and about 38,000 die from head
injury before being admitted to a hospital.
[0004] Brain damage may also be the result of a lack of oxygen. For
instance, hypoxic-ischemic encephalopathy, or HIE, is a condition
that occurs when the brain has been deprived of an adequate oxygen
supply. Infants that have incured hypoxic-ischemic encephallopathy
(HIE) constitute about 23% of neonatal deaths worldwide.
[0005] Current clinical practice for the treatment of brain edema
cases is to use an invasive procedure called craniotomy.
Experimental evidence for the beneficial or detrimental role of
decompression craniotomy after traumatic brain injury are scarce.
Recent researches and studies on mice suggest that a craniotomy may
be a useful therapeutic option after traumatic brain injury (TBI)
in humans, provided that it is applied early.
[0006] In infants with hypoxic-ishemic encephalopathy, therapeutic
hypothermia is more beneficial for edema reduction if applied
early. In spite of improvements in outcome since the introduction
of therapeutic hypothermia as a treatment modality, 55% of treated
infants die or have adverse neurodevelopmental outcomes. Additional
neuroprotective strategies are needed for improving the outcomes of
affected infants.
[0007] The detection of edema may be based on computed tomography
(CT) scans or magnetic resonance imaging (MRI). However, since both
CT and MM are expensive, not every medical facility has such
equipment. Also, since such equipment is not portable and CT has
radiation exposure, such equipment cannot be used in the field or
for continuous, bedside monitoring. Once edema is detected, its
progression is usually monitored by using an intracranial pressure
(ICP) monitoring sensor which is invasive and can cause
complications.
[0008] Early detection of brain edema can help clinicians in the
timely identification of patients that are in need of surgery or
other types of therapy and thus, improve the outcome of such
therapies. Thus, early detection of brain edema may be effective
for reducing the development of more serious brain injury and
related disabilities and can lessen the costs of treating a brain
injury.
[0009] In addition, the ability to monitor cerebral autoregulation
may provide important information for the care of some patients.
Cerebral autoregulation is the physiological mechanism that
maintains cerebral blood flow an appropriate level during changes
in blood pressure. By way of example, an accurate assessment of
cerebral autoregulation may guide in the selection and level of
treatment regimes from mild to intense using hypothermia to drug
treatments and hence improve treatment outcomes and quality of life
of patients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Various features of the embodiments described in the
following detailed description can be more fully appreciated when
considered with reference to the accompanying figures, wherein the
same numbers refer to the same elements.
[0011] FIG. 1 is a perspective view of a part of a system for
monitoring brain edema and/or for assessing cerebral autoregulation
according to an embodiment.
[0012] FIG. 2 is an elevational view of separate and identical left
and right sensors or probes of the system of FIG. 1.
[0013] FIG. 3 is a perspective view of a control box, data
acquisition card, and presentation computer of the system of FIG.
1.
[0014] FIG. 4 is a graph showing temperature dependence of
phosphate buffered saline, wherein "A" represents absolute spectra
at 20.degree. C. (via continuous line) and at 40.degree. C. (via
dashed line) and in which "B" represents a difference spectrum
(40-20.degree. C.).
[0015] FIG. 5 is a graph showing temperature dependence of Hb,
wherein "A" represents absolute spectra at 20.degree. C. (via
continuous line) and at 40.degree. C. (via dashed line) and in
which "B" represents a difference spectrum (40-20.degree. C.).
[0016] FIG. 6 is a graph showing temperature dependence of
HbO.sub.2, wherein "A" represents absolute spectra at 20.degree. C.
(via continuous line) and at 40.degree. C. (via dashed line) and in
which "B" represents a difference spectrum (40-20.degree. C.).
[0017] FIG. 7 is a graph showing an absorption spectrum of water
over a temperature range of 15 to 60.degree. C. with temperature
increments of 5.degree. C.
[0018] FIG. 8 is a graph showing a differential absorption spectrum
of water over a temperature range of 15 to 60.degree. C. with
temperature increments of 5.degree. C.
[0019] FIG. 9 is a graph showing changes in DPF relative to
wavelength.
[0020] FIG. 10 is a perspective view of a clinical prototype edema
monitoring system for laboratory testing using head mimicking
phantoms according to an embodiment.
[0021] FIG. 11 is a graph showing continuous intensity measurements
using the monitoring system of FIG. 10 for a 6 hour period.
[0022] FIG. 12 represents intensity measurements using the
monitoring system of FIG. 10 during the first 50 seconds of a 6
hour drift test and the first 50 seconds of a 3 hour drift
test.
[0023] FIG. 13 is a graph representing changes in the absorption
spectrum of water due to changes in temperature from 0.5.degree. C.
to 90.degree. C. at around 730 nm.
[0024] FIG. 14 is a graph representing changes in the absorption
spectrum of water due to changes in temperature from 0.5.degree. C.
to 90.degree. C. at around 850 nm.
[0025] FIG. 15 is a graph representing changes in the absorption
spectrum of water due to changes in temperature from 0.5.degree. C.
to 90.degree. C. at around 960 nm.
[0026] FIG. 16 is a graph representing changes in NIR intensity
levels at 730, 850 and 960 nm wavelengths due to changes in
temperature between 36.degree. C. and 41.degree. C.
[0027] FIG. 17 is a graph representing results of four consecutive
measurements of 20 minutes every 3 hours on a liquid phantom
without (first graph) and with diffuse edema (last graph) where
edema is introduced in between 2nd and 3rd set of recordings (the
signal levels change in the measurements in the first and fourth
graphs due to diffuse edema).
[0028] FIG. 18 is a graph representing the results of a first of
two consecutive measurements of 20 minutes within 3 hours on a
solid phantom without edema (beginning of the figure) and with
edema (introduced .about.5 min in the figure where signal levels
change and remain the same over time).
[0029] FIG. 19 is a graph representing the results of a second of
two consecutive measurements of 20 minutes within 3 hours on a
solid phantom with edema (signal levels remain the same over
time).
[0030] FIG. 20 is a graph representing diffuse edema results of
MBLL for Hb, HbO.sub.2, water and Hbt at 3 cm source detector
separation where 10% water was added at .about.90%, .about.50% and
.about.10% saturation condition.
[0031] FIG. 21 is a perspective view of laboratory equipment used
during focal edema tests according to an embodiment.
[0032] FIG. 22 is a graph representing focal edema results after
MBLL for Hb, HbO.sub.2, water and Hbt at 3 cm source detector
separation where 20 cc volume water balloon was inserted at
.about.90%, .about.50% and .about.10% oxygen saturation conditions
obtained using light sources at 730, 850 and 960 nm.
[0033] FIG. 23 is a graph representing focal edema test results
when a water balloon filled with 10 ml of water is dipped in and
taken out of the brain region of the phantom repeatedly for
<10%, .about.50% and >90% oxygen saturation conditions.
[0034] FIG. 24 is a graph representing focal edema test results
when a water balloon filled with 30 ml of water is dipped in and
taken out of the brain region of the phantom repeatedly for
<10%, .about.50% and >90% oxygen saturation conditions.
[0035] FIG. 25 is a graph representing hematoma model results after
MBLL for Hb, HbO.sub.2, water and Hbt at 3 cm source detector
separation where 20 cc volume rubber balloon filled with blood was
inserted at .about.90%, .about.50% and .about.10% oxygen saturation
conditions.
[0036] FIG. 26 is a chart representing edema monitoring device
results for raw intensity measurements at 3 cm source detector
separation on the right side of a human patient's brain.
[0037] FIG. 27 is a chart representing edema monitoring device
results for change in blood (Hb and HbO.sub.2) and water contents
of a human patient's brain.
[0038] FIG. 28 is a chart representing edema device recordings vs
ICP values.
[0039] FIG. 29 is a chart representing edema device recordings vs
CPP values.
[0040] FIG. 30 is a chart representing edema monitoring device
results for raw intensity measurements at 3 cm source detector
separation on the right side of a patient's brain.
[0041] FIG. 31 is a chart representing edema monitoring device
results for change in blood (Hb and HbO.sub.2) and water contents
of a human patient's brain.
[0042] FIG. 32 is a chart representing edema device recordings vs
ICP values.
[0043] FIG. 33 is a chart representing edema device recordings vs
CPP values.
[0044] FIG. 34 is charts representing overall recordings for Nx and
HI piglets.
[0045] FIG. 35 is a graph showing average NIRS water signal for Nx
and HI piglets.
[0046] FIG. 36 is a graph showing ICP for Nx and HI piglets.
[0047] FIG. 37 is a graph showing wet/dry ratio measurements for Nx
and HI piglets.
[0048] FIG. 38 is a chart representing averaged 2 minute signal
epochs following drug injection for Hypoxic piglet.
[0049] FIG. 39 is a chart representing averaged 2 minute signal
epochs following drug injection for Normoxic piglet.
[0050] FIG. 40 is a graph showing averaged minimum dip values in
Hb, HbO2 and water signal epochs following drug injection for
Hypoxic and Normoxic piglets.
[0051] FIG. 41 is graphs showing correlations between NIRS-derived
water signal and ICP and wet/dry ratio measurements.
DETAILED DESCRIPTION
[0052] For simplicity and illustrative purposes, principles of
embodiments are described herein by referring primarily to examples
thereof. In the following description, numerous specific details
are set forth to provide a thorough understanding of the
embodiments. It will be apparent to one of ordinary skill in the
art that the embodiments may be practiced without limitation to
these specific details. In some instances, well known methods and
structures have not been described in detail so as not to
unnecessarily obscure the embodiments.
[0053] "Patient" or "subject" as used herein means a mammalian
animal, including a human, a veterinary or farm animal, a domestic
animal or pet, and animals normally used for clinical research.
More specifically, the subject of these methods, systems and
devices is a human.
[0054] According to an embodiment, a system, device and method for
quantitatively monitoring and evaluating changes in water and
hemoglobin content in the brain in a non-invasive manner are
provided. Such a system or device may be used for real-time
detection and monitoring of brain edema and/or for an assessment of
cerebral autoregulation.
[0055] Embodiments may be provided in the form of a relatively
affordable, hand-held, non-invasive, portable, detection and
monitoring device that is able to significantly enhance and aid
current clinical practices and treatments of patients. For
instance, the device may be able to help first responders and other
clinicians to make rapid and accurate on-site clinical decisions
for treatment of patients with brain edema or other brain damage.
As one contimplated example, the device may be beneficial for
military use where early detection and rapid treatment of brain
edema, one of the most common blast related injuries in the
battlefield, is critical to prevent development of severe brain
injury.
[0056] In addition, embodiments of the device and method may
provide important information relative to the experience of a prior
hypoxic event by a patient which is not otherwise possible with any
existing methodologies. Existance of a hypoxic event can guide
therapeutic procedures including their selection and intensity.
Without such knowledge, doctors and other care givers may only
monitor immediate vital signs and attempt to make judgements on the
administration of different forms of therapies according to the
vital signs and their related outcomes by trial and error. In
contrast, with device and method of the embodiments disclosed
herein, doctors and other care givers may monitor signal changes as
measured by the non-invasive device which will be representative of
cerebral autoregulation after the administration of different
medications for some period of time, for instance, in a matter of
minutes. In this manner, the doctor may be able to determine if a
hypoxic event had taken place at a prior time and select a most
appropriate type and amount of therapy and continue to monitor
their outcomes by monitoring not just the vital signs, but also,
changes in cerebral autoregulation.
[0057] According to one contemplated embodiment, the device may be
a near-infrared (NIR) based device that relies on optical
techniques derived from the physical principles of light absorption
and reflectance to detect changes in the water and oxygenated
(oxyHb) and deoxygenated hemoglobin (deoxyHb) content in the brain.
Most biological tissues are relatively transparent to light in the
NIR range between about 700-1000 nm, which is commonly referred to
as an optical window. This is primarily due to the fact that within
this optical window, the absorbance of the main constituents in
human tissue (i.e. water, oxyHb and deoxyHb) is small, allowing
light to penetrate the tissue. Fortunately, the absorption spectra
of water, oxyHb and deoxyHb in the optical window remain
significantly different from each other, which allows spectroscopic
separation of these compounds to be possible via the use of a few
sample wavelengths.
[0058] Thus, according to an embodiment, a device may operate at
wavelengths tuned for the extraction of water and hemoglobin
concentration within the brain. Since hemoglobin content can
change, for example, due to hematoma development together with
changes in the water content due to edema, the device may be
designed to monitor the changes in all of these absorbers
simultaneously. By way of example, the NIR-based monitoring sensor
may house one or more light sources that irradiate light at
wavelengths, for instance, of 730 nm (for deoxyHb concentration
extraction), 850 nm (for oxyHb concentration extraction) and 940 or
960 nm (for water concentration extraction) and photodetectors to
detect the light after it interracts with tissue.
[0059] The device may also house a temperature measurement
mechanism, for instance, a built-in thermistor, to guide in
selection of appropriate parameters in algorithms for correct
extraction of the above referenced chromophore. Since fever may
occur in patients with edema development and since hypothermia may
be used as a treatment technique for HIE patients, changes in
temperature may be taken into account for reliable measurement of
changes in oxyHb, deoxyHb and water content of such patients.
[0060] The device may also have and apply appropriate algorithms
for the identification and correction of signal changes in device
measurements that may be due to the positioning of an unconscious,
critically ill patient where the laying position of the patient (on
their back or side) may be required to be adjusted frequently
during their stay in an intensive care unit. This and other
additional algorithms may be used to increase the reliability and
effectiveness of measurements taken by the device.
System Components
[0061] The system may be in the form of a portable, point of care,
near-infrared (NIR) based imaging device that utilizes various
hardware components and applies various advanced algorithms that
may be designed for different purposes, such as to rapidly detect
and monitor brain edema and assess cerebral autoregulation. An
example of a system 10 is best shown in FIG. 1-3.
[0062] The main components of the system 10 include one or more
lightweight probes or sensors that may be designed to cover the
forehead of a patient and/or parts thereof. As an example, a pair
of separate and identical sensors, such as left probe 12 and right
probe 14, is shown in FIG. 1. The system 10 may also include a
control box 16 for data acquisition, a power supply for the control
box (not shown), and a computer or electronic processing device 18
having or providing access to data analysis software. As shown in
FIG. 3, the computer 18 may have a display for displaying and
presenting measurements taken by the device.
[0063] As best shown in FIG. 2, each of the sensors, 12 and 14, has
at least one LED light source 20 and two light detectors, 22 and
24, that may be spaced, for instance, 3 cm and 4 cm, respectively,
from the light source 20. In use, one of the sensors 12 is adapted
to be placed on a left side of the patient's forehead and the other
sensor 14 is adapted to be placed on a right side of the forehead.
As best shown in FIG. 1, each of the sensors, 12 and 14, may be
connected to the control box 16 via wires 26 via an intermediate
unit 28 housing signal splitters and/or thermal shutdown circuits.
Of course, the sensors or any of the other components may also be
adapted to communicate via wireless communications and various ones
of the units may be combined and housed in a single unit or
provided as separate units and/or be provided by one of more
electronic processing units.
[0064] Each of the sensor, 12 and 14, may be flexible and provided
in the form of a modular design consisting of two parts: an
identical, reusable, flexible circuit board 30 (see FIG. 2) that
carries infrared sources and detectors; and a disposable,
single-use cushioning material 32 that serves to attach the sensor
to the forehead of the patient, for instance, with a medical grade
adhesive tape. In FIG. 2, the left probe 12 is shown with
cushioning material removed and the right probe 14 is shown with
cushioning material applied. The cushioning material may be a black
foam material for providing comfortable usage and sealing for
possible light and electrical leakage.
[0065] The flexible circuit of the sensors/probes provides a
reliable integrated wiring solution, as well as enables consistent
and reproducible component spacing and alignment. Because the
circuit board and cushioning material are flexible, the components
are able to move and adapt to various contours of the front of the
patient's forehead, thus allowing the sensor elements to maintain
an orthogonal orientation to the skin surface, which dramatically
improves light coupling efficiency and signal strength. As an
alternative, the pair of sensors, 12 and 14, may be provided in the
form of a single full head version of a flexible sensor that may
extend on both the right and left sides of the forehead as a single
continuous unit. The area of the sensor/probe is preferably small
to reduce any possible irritation that an adhesive may possibly
cause on a subject's forehead.
[0066] Accordingly, the sensor or probes, 12 and 14, are designed
to simultaneously and separately collect data from right and left
hemispheres of a patient for comparison purposes which may be
particularly useful should unilateral edema exist. In one
contemplated embodiment for a device for edema monitoring and
cerebral autoregulation assessment, the light sources are light
emitting diodes (LEDs) that emit light waves at 730, 850 and 940 nm
wavelengths to focus light absorption to deoxygenated hemoglobin
(Hb), oxygenated hemoglobin (HbO.sub.2) and water, respectively. By
way of example, the light source 20 may include an Epitex LED
capable of emitting light at wavelengths of 730 nm and 850 nm and a
Roithner LaserTechnik LED cable of emitting light at 940 nm, and
the photo detectors, 22 and 24, may be Burr-Brown silicon
photodiodes having a 2.24 mm by 2.24 active area. Thus, the system
10 may enable changes in water concentration over time, changes in
oxy-hemoglobin concentration over time, and changes in
deoxy-hemoglobin concentration over time to be detected.
[0067] The control box 16 may host analog filters and amplifies and
may be connected to a data acquisition board (DAQ) 34 which is
connected to the computer 18. The DAQ 34 may be designed to be
responsible for switching the light sources 20 and photo detectors,
22 and 24, which collect the reflected light. Thus, operation of
the light sources at the three wavelengths may be controlled by
data acquisition software on the DAQ 34 and powered by driving
current.
[0068] The probes or sensors, 12 and 14, may house a thermistor to
provide measurements on patient's temperature. These measurements
may also be used in parameter adjustment for more reliable
separation of Hb, HbO.sub.2 and water content. By way of example,
the thermistor may be a Digi-Key Part Number 615-1016-ND, US Sensor
103JG1J.
[0069] The temperature information may provide a safety mechanism
for the device such that, if there is excessive skin heating caused
by the device (e.g. due to a possible shortage or failure), the
system 10 will automatically power off. The DAQ 34, control box 34,
and/or unit 28 may have circuitry that collects data from the
thermistor and causes the system 10 to power off when needed which
can also be used for further parameter adjustment.
[0070] The light source for the NIR device uses light emitting
diodes (LEDs) which provide a very compact wavelength light source.
The LEDs provide highly monochromatic sources with very fast time
sequencing (50 msec) and are available at 730, 850 and 940 nm. A
power consumption of .about.0.2 watt, time shared at 1 msec is
typical. No optical filter is necessary and detectors are
circumferentially mounted (non-laser light).
[0071] The LEDs generate 0.016 Watt/cm.sup.2 per second per
wavelength. The three wavelengths are used individually, in a
sequenced manner for about 1 msec each, i.e., the NIR system does
not use multiple wavelengths at a given time. In addition, after
each wavelength has been pulsed, there is an intermittent period
when all three wavelengths are off before starting the next
sequence. This intermittent period provides a benefit of allowing
any heat generated by the LED to disperse. Therefore, the light
intensity associated with any given length of exposure to the near
infrared LEDs is less than the light intensity associated with an
equivalent exposure to solar spectrum.
[0072] The maximum power of the system may be 5 mWatt, there may be
four measurement channels, data sampling rate may be 2 Hz to 1 kHz,
and the main voltage may be provided by a medically graded power
supply 110-220 VAC or 7.2 volt battery. Of course, these may be
modified as needed. Accordingly, two light sources composed of
three LEDs at 730, 850 and 940 nm wavelengths located on the
contra-lateral sides of the sensors can be powered and data can be
collected from four light detectors on the sensors.
Data Analysis
[0073] Since water has higher absorption around 940 nm as compared
to other chromophores (oxyHb and deoxyHb), the light source 20
emitting light at a wavelength of about 940 nm focuses the
attenuation of light primarily to changes in the concentration of
water content in the brain. In addition, because the absorption of
water and other chromophores such as melanin, lipid, hemoglobin,
etc. are relatively small around 940 nm, light can penetrate tissue
around this wavelength and a signal of sufficient strength can
readily be detected by the photodetectors, 22 and 24, after light
interacts with the tissue for reliable spectroscopic separation.
The attenuation of light at the two other wavelengths, 730 nm and
850 nm, is for detecting changes in the concentration of the Hb and
HbO.sub.2, respectively. With the use of these three wavelengths
together, spectroscopic measurements for the extraction of the
primary chromophores of interest in the tissue such as water, oxyHb
and deoxyHb can be performed.
[0074] Accordingly, changes in concentrations of water, oxyHb and
deoxyHb due to edema can be reliably measured even in the presence
of hemorrhage or hematoma which can occur simultaneously with edema
or regardless of changes in the blood content due decrease in
cerebral blood flow (CBF) or increased cerebral blood volume which
are very common consequences of traumatic brain injury. Thus, the
embodiment disclosed herein monitors both the hemoglobin and water
contents in the brain.
[0075] The system 10 is designed to collect measurements from a
patient over a period of time. During this time, regardless of
edema development, changes in NIR measurements may occur due to
signal drifts, temperature changes, cognitive activity, hematoma
development, and the like.
[0076] Algorithms are provided to process the NIR measurements. The
NIR system first measures optical density (OD) changes at the three
wavelengths (730, 850 and 940 nm). By measuring optical density
(OD) changes at three wavelengths where water, HbO.sub.2 and Hb are
the main absorbers, the relative change in water, Hb and HbO.sub.2
versus time are obtained using the modified Beer-Lambert law
(MBLL). If the intensity measurement at an initial time is I.sub.0
(baseline), and at another time is I, the relative change in OD due
to the variation in the concentrations of chromophores,
.DELTA.C.sub.Water, .DELTA.C.sub.Hb and .DELTA.C.sub.HbO2 during
that period is found as:
.DELTA.OD.sup..lamda.=-log
10(I.sup..lamda./Io.sup..lamda.)=(.epsilon..sup..lamda..sub.Hb
.DELTA.C.sub.Hb+.epsilon..sup..lamda..sub.HbO2+.epsilon..sup..lamda..sub.-
Water .DELTA.C.sub.Water) d PDF.sup..lamda.
where d is the distance between light source and light detector,
DP.sup..lamda. is the wavelength dependent differential path length
factor, .epsilon..sup..lamda..sub.Water,
.epsilon..sup..lamda..sub.Hb and .epsilon..sup..lamda..sub.HbO2 are
the molar extinction coefficients of water, Hb and HbO.sub.2,
respectively. Measurements performed at three different wavelengths
allow the calculation of .DELTA.C.sub.Water, .DELTA.C.sub.Hb and
.DELTA.C.sub.HbO2 solving the equation found by using the
.DELTA.OD.sup..lamda. relationships:
[ .DELTA. C Hb .DELTA. C HbO 2 .DELTA. C Water ] = A - 1 [ .DELTA.
OD 730 nm .DELTA. OD 850 nm .DELTA. OD 960 nm ] where ##EQU00001##
A = d [ DPF 730 Hb 730 DPF 730 HbO 2 730 DPF 730 Water 730 DPF 850
Hb 850 DPF 850 HbO 2 850 DPF 850 Water 850 DPF 960 Hb 960 DPF 960
HbO 2 960 DPF 960 Water 960 ] ##EQU00001.2##
[0077] After traumatic brain injury or a hypoxic-ischemic event,
edema and hematoma can develop separately or together at the same
time or one after the other. In addition, when edema develops after
brain injury, swelling in the brain can cause elevation of
intracranial pressure and reduction of cerebral blood flow which
can further change the blood oxygenation and cause hypoxia or
ischemia. Regardless of such situation, since measurements will be
obtained from the frontal cortex, any brain activity can cause
changes in HbO.sub.2 and Hb levels which can in turn affect signal
levels. Hence, changes in blood content should be extracted and
closely monitored together with the water content for the reliable
and robust monitoring of edema. With the implementation of the
light sources at three wavelengths, where each one is specifically
selected to focus the light absorption to one chromophore (730 nm
for Hb, 850 nm for HbO.sub.2, and 940 nm for water absorption),
water and blood content within the tissue can be effectively
monitored.
[0078] The absorption spectrum of water, and also other chromophore
such as HbO.sub.2 and Hb, within the near infrared range changes
related with change in temperature as shown in FIGS. 4-8.
Temperature change can happen in patients with edema development or
it can be a result of selected therapy like hypothermia. Since the
system will be able to measure changes in the temperature by the
use of the thermistor simultaneously with light attenuation, the
signal processing component of the device will have the capability
to automatically adjust the signal separation algorithm embedded in
the system and use the temperature information to adjust the
extinction coefficients in the MBLL accordingly for more reliable
separation in Hb, HbO.sub.2, and water content.
[0079] In addition, DPF changes, not only with wavelength, but also
with source detector separation. For example, see FIG. 9. In the
signal processing component of the device, appropriate DPF values
will be embedded for different wavelengths and source detector
separations in the MBLL algorithm. DPF further changes depending on
variations in oxygen saturation. Hence, necessary adjustments are
made to the DPF values when using it in MBLL for the reliable
extraction of the chromophores by reducing crosstalk between
measurements. Since the device can measure Hb and HbO.sub.2 with
the use of light sources at 730 and 850 nm wavelengths, it
intrinsically has the capability of measuring local tissue oxygen
saturation. Using the oxygen saturation measurements that can be
obtained by the device, adjustments to DPF values can be
established in the system for more reliable separation of water
content from the remainder of the chromophores.
[0080] A common procedure in intensive care units is the
repositioning of a patient during their prolonged stay in bed when
they are unconscious in order to avoid bedsores. The patient
population on which the system may be used may also primarily be
critically ill patients who may be unconscious. Head movement and
change in baseline measurements due to head movement, presents a
problem for the NIR measurements. Even in patients that are awake,
there can be head movement that can cause change in baseline values
regardless of edema or hematoma development.
[0081] Thus, in addition to the above referenced parameter
adjustments in the signal analysis component of the proposed
device, the system will also have algorithms to identify and remove
artifacts due to head movement or patient laying position
adjustment by using the measurements obtained from contralateral
sides (expected to be in reverse direction for artifacts), the
timing and amount of change in the signal values (larger amount
changes in shorter time as compared to changes that can be expected
when there is edema or hematoma development). In such cases, when
there is head movement or the laying position of a patient is
changed (from back to right side or to left side) the baseline
amount of blood and water will change accordingly (it will pool on
the side that the patient is laying on or moved his/her head down
to and move away from the other side). This type of signal change
may be identified and corrected from the measurements. Certain
markers can be put on the measurements at the time of patient
repositioning which can be used in the identification of such
signal changes. However, considering that medical personnel will be
busy in taking care of patients, this type of marker placement can
be missed and hence, an automatic manner for the identification of
such baseline shifts may be utilized.
[0082] For example, one manner of automatically identifying head
movement is by checking the rate and amount of change in the signal
levels and comparing the right and left side measurements from the
separate sensors. Edema or hematoma development is typically a slow
process (minutes to hours) as compared to head movement or laying
position change related differences in the measured signals (in
seconds). The amount of change in the signal over a smaller period
of time is also typically larger. Thresholds in signal level
changes over time can be found and used to identify such
regions.
[0083] Also, the change in the signal should be reverse in left and
right side measurement when a repositioning happens. When laying
position of the patient is moved from left side to right side (or
back to right side or left to back side), blood should move away
from the left side to the right side causing an increase in light
absorption on the right and a decrease on the left. It will be
reversed when the patient is moved from right to left side (right
to backside or back to left side). Thus, there can be opposite
changes in left side and right side channel measurements of the NIR
system that can be used in the identification of baseline shifts
due to head movement or patient repositioning.
[0084] One embodiment of a method of use of the NIR system or
device described herein is for a method of assessing cerebral
autoregulation in a mammalian subject. This method involves
administering to the subject intravenously a composition comprising
saline and an anesthetic; and obtaining multiple measurements from
the subject over time of oxygenated (oxyHb), deoxygenated
hemoglobin (deoxyHb) and water using near infrared spectroscopy
(NIR). The multiple measurements obtained from the subject are
evaluated against a reference standard to identify any change in
the measurements of oxyHb, deoxyHb and water characteristic of
hypoxic injury or aberrent cerebral autoregulation. As described
above, such measurements may be obtained by use of an NIRS sensor
in contact with the tissue of the forehead of the subject. The NIRS
measurements are sequentially made within a single time period,
i.e., are substantantially simultaneous measurements of oxyHb,
deoxyHb and water at each time point.
[0085] In certain embodiments, the method also involves obtaining
from the subject baseline measurements of oxyHb, deoxyHb and water
using NIR prior to administration of said composition; and
correcting the additional measurements by subtracting the baseline
measurements prior to analysis.
[0086] The composition infused into the subject during this method
is generally an aqueous solution. Alternatively or in addition, the
composition is accompanied by administration of an anesthetic or
paralytic, either by the same or different routes. In one
embodiment, the aqueous solution comprises normal saline solution.
In another embodiment, the solution comprises sodium bicarbonate.
In still another embodiment, the composition comprises a sugar,
e.g., dextrose. In another embodiment, the composition contains an
analgesic agent; and in a further embodiment, the analgesic agent
is administered seperately from the composition infused. Among
useful analgesic agents is the analgesic agent Fentanyl or those
mentioned herein. Other known analgesic agents may be selected by
one of skill in the art with regard to this teaching. In still
another embodiment the compositions comprises a paralytic agent;
and in another embodiment, the paralytic agent is administered
seperately from the composition infused. Among useful paralytics is
vecuronium. Other known paralytic agents may be selected by one of
skill in the art with regard to this teaching. In other
embodiments, the composition contains saline and an analgesic
agent. In another embodiment, the composition contains saline and a
paralytic agent. In still other embodiments, the composition
comprises saline, an analgesic agent and a paralytic agent. One of
skill in the art may select other components suitable for inclusion
in to the composition.
[0087] As one example, a suitable composition comprises one or more
of a concentration of 10 ml/kg weight saline, a concentration of 50
mcg/kg Fentanyl, and a concentration of vecuronium of about 0.1
mg/kg.
[0088] The composition is in one embodiment, administered at a rate
of infusion of between 10 to about 20 ml/minute. Thus in certain
embodiments, the infusion rate is 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20 or more ml/minutes, including both endpoints and any
fractional amount between the integers identified herein. The
infusion of the composition generally occurs over a time period of
about 1 to 2 minutes, including each endpoint and any fractional
amount of the minutes therebetween. Other embodiments are also
contemplated in which the infusion occurs over less than 60
seconds, e.g., down to about 10 seconds, or over a time period of
greater than 2 minutes.
[0089] The volume of composition infused into the subject generally
ranges from about 25 to about 40 ml, including both endpoints. Thus
the infusion volume may be selected from 25, 26, 27, 28, 29, 30,
31, 32, 33, 34, 35, 36, 37, 38, 39, and 40 ml volumes, including
both endpoints and any fractional amount between the integers
identified herein.
[0090] The route of administration of the infusions may be selected
from any known route found appropriate by a physician. In one
embodiment, the administration route is intravenous. In another
embodiment, the administration route is by inhalation.
[0091] It should be understood by one of skill in the art that
following the teachings of this specification, a physician
conducting this assessment may select the appropriate infusion
rate, volume, route of administration and time period, as well as
the components of the composition.
[0092] One particular example of the method involves administration
of the composition comprising normal saline solution 10 ml/kg/dose
rapid i.v. push over 1-2 minutes, 8.4% sodium bicarbonate solution
2 ml/kg/dose i.v. over 1-2 minutes, and 5% dextrose 1/2 normal
saline solution i.v. 4-5 ml/kg/hr. Anesthesia was induced using
inhalational isoflurane 4%, and maintained with nitrous oxide
inhalational anesthetic 79-94% blended with oxygen FiO2 0.06-0.4
and adjusted to ensure proper depth of anesthesia and oxygentation.
Adequate analgesia and sedation was ensured by giving additional
doses of Fentanyl 50 mcg/kg/dose q 1-2 hours as needed. Paralytic
agent vecuronium 0.1 mg/kg/dose (alternative: rocuronium) was
administered q1-2 hours as needed to avoid any motion
artifacts.
[0093] According to the above example of the method, the
composition is administered intravenously for saline, dextrose,
bicarbonate, analgesic and paralytic agents listed above, as
intravenous route is the most effective route to achieve rapid
plasma levels for intended effects. Anesthetic agents are
administered by inhalational route.
[0094] The evaluation or analysis of the subject's NIR data is also
part of the method for assessing cerebral autoregulation. This
analysis involves evaluating and interpreting the subject's data at
various timepoints against a selected reference standard. The
selection of the reference standard is made by the physician to
diagnose or identify the injury, its likely time or occurrence,
and/or monitoring the subject's recovery from injury or response to
treatment. The terms "Reference", "Reference Standard" or "Control"
as used herein mean a level, standard or profile of reference NIR
data e.g., OD or other signals detected by the NIR devices used in
the methods described herein. To permit proper determination or
identification of disease or injury based on the NIR measurements
of oxyHb, deoxyHb and water, and optionally temperature, oxygen
saturation or other data obtained from a subject, the subject's
measurements are compared to reference.
[0095] In one embodiment, the reference standard is obtained from a
reference human subject or population that is healthy and without
any brain injury or disease. In one embodiment, the reference
standard is obtained from a healthy reference human (or appropriate
animal) subject or population that has not been infused with the
saline and anesthetic composition used in some of the methods
described herein. This reference human subject or population is a
"normoxic" reference. In another embodiment, the normoxic reference
standard is obtained from a healthy reference human subject or
population that has been infused with the saline and anesthetic
composition and has been monitored with NIRS measurements over
identified periods of time before, during or after this
infusion.
[0096] In still another embodiment, the reference standard is
obtained from a reference human (or appropriate animal) subject or
population that has had a hypoxic brain injury, edematous injury,
or other brain injury event, i.e., a "hypoxic" reference. In one
embodiment, this hypoxic reference subject or population has not
been infused with the saline and anesthetic composition described
herein. In another embodiment, the hypoxic reference standard
subject or population has been infused with the saline and
anesthetic composition and has been monitored with NIRS
measurements over identified periods of time before, during or
after this infusion.
[0097] In still another embodiment, the reference standard or
control against which the tested subjects NIRS data is compared is
a hypoxic reference subject or population which has been treated
for hypoxic injury. This reference standard would be useful in
monitoring the cerebral autoregulation of a patient undergoing
treatment for a hypoxic injury. In still another embodiment, the
reference standard is obtained the same subject undergoing testing
and comprises the NIRS data from an earlier timepoint in testing.
In another embodiment, the reference standard is a combination of
two or more of the above reference standards.
[0098] In certain embodiments, the reference standard utilized is a
standard or profile derived from a single reference subject. In
other embodiments, the reference standard utilized is a standard or
profile derived from averaged data from multiple reference
subjects. The reference standard, in various embodiments, is a
mean, an average, a numerical mean or range of numerical means, a
numerical pattern, or a graphical pattern created from the NIRS
data derived from a reference subject or reference population.
Selection of the particular class of reference standards, or
reference population depends upon the use to which the
diagnostic/monitoring methods described herein are to be put by the
physician.
[0099] Based on this evaluation and the relative changes in the
subject's NIR data for oxyHb, deoxyHb and water compared to one or
multiple reference standards, the physician can identify the
occurrence of a hypoxic event or injury or disease in the subject
by identifying a characteristic decrease in the NIR values
occasioned by hypoxic injury. The same method is useful for
monitoring and adjusting therapy for a subject recovering or under
treatment for such a hypoxic injury.
EXAMPLES
[0100] The following examples are provided to demonstrate the
effectiveness of the above referenced system and device and to
demonstrate various methods of use. The examples include test
results and methods performed on synthetic human brain-like
phantoms, human adult patients having serious head injuries, and
piglets.
Example 1
Synthetic Human Brain Like-Phantoms
[0101] An overall edema monitoring system 110 according to an
embodiment having a NIR sensor 112, data acquisition box 114, and
presentation computer 116 is shown in FIG. 10 and was used during
laboratory experimentation on a head mimicking phantom 118. This
pre-clinical prototype is capable of measuring changes in water and
blood content of the tissue within the head beneath the sensor
collecting data on contra-lateral sides of the forehead at depth
.about.2 cm with a sampling rate of 2 Hz. In all the phantom tests
reported here, the NIR sensor was used with light sources at 730,
850 and 960 nm wavelengths. A wavelength of 940 nm could be used in
replace of the 960 nm wavelength and, in practice, has been found
to provide a desired increase in measured signal strength.
[0102] The proposed system 110 was used to collect measurements
over a period of time for monitoring purposes. During this time,
regardless of edema development, changes in NIR measurements can
occur due to signal drifts, temperature changes, cognitive
activity, hematoma development, and the like. Some of these issues,
such as the ones related with penetration, signal drift and
temperature are discussed below in greater detail.
[0103] Penetration: The light sources in the NIR device 112 are
driven sequentially and the light detectors collect light
accordingly to generated data samples at each wavelength
separately. In the data collection or aquistion box 114, all light
sources were driven at the same current level that was specifically
selected to guarantee penetration and eliminate the possibility of
saturation at 730 and 850 nm wavelengths. With the addition of
another light source at 960 nm wavelength, it was necessary to
first make sure that there was no saturation and enough penetration
if light source at 960 nm is driven with the same current as the
others.
[0104] The signal levels at 960 nm are first tested for saturation
and penetration on human head mimicking phantom 118 before
performing any further phantom tests on edema detection and
monitoring. It is usually impractical to switch the driving current
back and forth for different light sources during sequential data
collection at different wavelengths. Instead it is preferred to use
the same driving current for each light source and adjust the
signal level accordingly by using optical filters on detectors to
eliminate saturation or to use multiple light sources at same
wavelength to increase signal level which will ensure penetration.
The signal levels of the prototype NIR sensor 112 are tested and
adjusted on the multi-layer liquid phantom 118 with optical and
physical characteristics mimicking an average adult human head with
absorption and scattering coefficients selected as .mu..sub.a=0.05
cm.sup.-1 and .mu..sub.s=10 cm.sup.-1 respectively as published in
literature. The tests suggested the use of two 960 nm light sources
together to ensure penetration at this wavelength and to eliminate
saturation. Alternatively, a single 940 nm light source can be used
instead of multiple 960 nm light sources.
[0105] Signal Drift: Prolonged NIR measurements on the fixed
phantom 118 of certain optical and physical properties are carried
out to detect the amount of signal drifts over time due to
electronics and optical components. Human head models were built
using the multi-layer liquid phantom with optical properties of an
average adult with .mu..sub.a=0.05 cm.sup.-1 and .mu..sub.s=10
cm.sup.-1 as published in the literature. NIR measurements were
continuously collected over several hours using the NIR system 110.
The drift test was performed three times where the first test was
for 2 hours, the second was for 3 hours and the last test was for a
6 hour period. Each time the phantom was rebuilt, it was rebuilt
with similar optical and physical properties as explained
above.
[0106] The light intensity measurements at 730, 850 and 960 nm
wavelengths during the 6 hour period test are shown in FIG. 11. The
mean of the maximum change or drift in the intensity after the
signal reaches steady state (.+-.standard deviation) over three
drift tests is found as 0.7.+-.0.4% for 730 nm, 0.5.+-.0.3% for 850
nm and 0.1.+-.0.03% for 960 nm. The mean.+-.standard deviation of
the slope of the time course of the recordings using the three
drift tests are found as (3.4.+-.4.2).times.10.sup.-4 for 730 nm,
(5.2.+-.3.5).times.10.sup.-4 for 850 nm and
(2.1.+-.0.9).times.10.sup.-4 for 960 nm. The change in the signal
due to drift are of several orders of magnitude less than the
change in the signal due to edema development as was found in
phantom tests for edema development (20-to-40% change in the NIR
signal intensity for a 1-to-3% increase in the water content in the
brain). Hence, signal drift in the embodiments of a NIR system, as
disclosed herein, will not generate a significant amount of change
in the signal levels that would otherwise confound decisions
regarding edema.
[0107] There is a transient period until the NIR signal reaches its
steady state value in the beginning 3 to 5 seconds of the
experiment after the light sources are powered for the first time.
In FIG. 12, the first 50 seconds of raw intensity measurements are
shown for 6 hour test and 3 hour test, respectively. As can be
seen, there is a transient period in the first 3 to 5 seconds of
recording until the signal reaches its steady state value which
stays at the same level relatively constantly in the following time
intervals. The transient period can be eliminated by discarding the
first 10 seconds of measurements within each recording.
[0108] Temperature: The absorption of water at different
wavelengths is highly dependent on temperature changes. In fact,
absorption of Hb and HbO.sub.2 also slightly changes with
temperature. The changes in the absorption coefficient of water at
different wavelengths have been previously reported, for instance,
as shown in FIGS. 13-15. As can be seen at around 730, 850 and 960
nm (the wavelengths that were used in the NIR sensor 112), there is
a large change in the absorption of water due to changes in
temperature from 0.5.degree. C. to 90.degree. C. Changes in
absorption of water due to temperature is especially important in
studies involving edema since patients who developed edema can also
experience changes in their temperature. Such changes related with
temperature are also observed in Hb and HbO.sub.2.
[0109] The change in the NIR signal was studied at different
wavelengths due to changes in temperature. A temperature test was
performed on the multi-layer liquid head phantom 118 as in the
signal drift studies with the same optical and physical
characteristics mimicking an average adult human head. The brain
compartment of the phantom 118 is placed over a heater 120 and the
temperature of the liquid within the brain layer was increased
linearly from ambient temperature 24.degree. C. to 42.degree. C.
over time. A magnetic stirrer was on during the course of the
experiment to keep the temperature of the liquid mixture in the
brain compartment homogeneous. Since experiments will be carried
out on humans, primarily of interest is the amount of change in the
signal for temperatures between 36.degree. C. to at most 41.degree.
C. The raw NIR intensity measurements at 730, 850 and 960 nm
wavelengths versus the temperatures between 36.degree. C. to
41.degree. C. are shown in FIG. 16. When the temperature increases,
absorption coefficient of water increases and hence detected light
intensity decreases at all wavelengths used even though the
concentrations of water and other absorbers within the phantom 118
remain constant. In the measurements, the change in the signal
levels between the temperature region of interest (between
36.degree. C. and 41.degree. C.) is around 4.2% for 730 nm, 3.8%
for 850 nm and 10% for 960 nm. These percent levels of change in
the NIR signals are comparable to signal level changes (20-to-40%)
due to 1-3% change in the water content of the brain as measured by
phantom tests for edema monitoring. Therefore, it is important to
pay attention to changes in the patient's temperature in order to
use correct absorption parameters in the extraction of water
content within the brain to detect and monitor edema development.
The device with built in temperature measurement capability can
automatically adapt the parameters in MBLL for more reliable signal
separation.
[0110] Phantom Tests for stability and reliability: The system 110
may be used in a continuous fashion or in an on-off type fashion
where it can be powered on and collect data and be powered off for
a period of time in between data collection sessions. A test of the
performance of the system 110 on solid and liquid phantoms in terms
of stability and reliability during continuous and on-off type of
measurements was performed. In real human subject testing, all the
changes in the measurements can be obtained continuously, every
hour or in 6 hour intervals will be calculated relative to the
first measurement period. Accordingly, the system 118 was tested
for capability of providing the same measurement levels in a stable
fashion in a next measurement period after the device was powered
off and then powered back on again as compared to the previous data
collection period given that there was no change in the water and
blood content in the medium.
[0111] For this purpose, two tests were performed. In a first set
of experiments to test the stability and reliability, the liquid
phantom 118 was used. Recordings of 20 minutes were obtained every
3 hours for four times. In the first two sets of recordings, the
water content in the brain layer of the phantom 118 was the same.
Between the 2nd and 3rd set of recordings, the water content was
changed by adding water to the brain layer of the phantom 118 to
mimic diffuse edema. In the last 2 sets of recordings, the
measurements obtained are when the same diffuse edema was present.
The results of this test are presented in FIG. 17. It was observed
from the results of these tests that the edema monitoring device
118 provides stable measurements when there is no change in the
water content of the brain. The change in the levels of raw
intensity measurements is negligible when the device records
continuously and also after it is turned off and back on again. The
device is also capable of reflecting the changes in the water
content repeatedly and reliably when it is present.
[0112] In a second set of experiments, a solid phantom was used
with a hole drilled on one side. In the first recording period of
20 minutes, the sensor was placed on a solid side of the phantom
that mimics the optical properties of a normal adult human head.
After 5 minutes, the sensor was moved on the hole side that was
filled with water mimicking focal edema. This first recording is
shown in FIG. 18. When the sensor recorded from the water filled
area, since the optical properties of the medium changed, the
values in the raw intensity measurements have changed after 5
minutes of recording. Then, the device was powered off and after 3
hours was re-started to collect measurements for 20 minutes from
the same location where focal edema model existed. These recordings
are shown in FIG. 19. In this second set of measurements where the
sensor was located on the focal edema location, it was observed
that the levels of raw intensity measurements started from the same
values as they were in the last portion of the first set of
measurements obtained 3 hours before and stayed the same for the
whole 20 minute period as would be expected since no change in the
water content was introduced.
Example 2
Testing and Evaluation of the Performance of the Clinical Prototype
Device in Edema and Hematoma Detection using Laboratory Tests under
Different Oxygen Saturation Conditions
[0113] Several phantom tests were performed using laboratory
prototype device measurements and the performance of the device and
the analysis algorithms in the separation of water and blood
content under different oxygen saturation conditions were
evaluated. The results of these tests were used not only for the
evaluation of the performance of the NIR system with 730, 850 and
960 nm wavelength light sources and algorithms based on MBLL in
edema detection and monitoring but also for the identification of
necessary adjustments required to improve their performance. The
tests justified the use of MBLL in resolving Hb, HbO.sub.2 and
water concentrations and the selection of 960 nm wavelength light
source to focus the measurements to the water content of the brain.
A 940 nm wavelength light source may also be utilized in place of
the 960 nm wavelength light source.
[0114] The following measurements and the results of the NIR data
analysis are used for the validation and evaluation of the
performance of the embodiments of an edema monitoring system and
data collection procedures disclosed herein. In these experiments,
focal and diffuse edema or hematoma development and changes in
oxygen saturation was modeled.
[0115] Phantom Preparation and Experimental Design: Different
scenarios were modeled that could happen after traumatic brain
injury or a hypoxic event on laboratory phantoms involving
different types of edema development in the presence and absence of
hematoma and blood oxygenation changes. In all of the experiments
used in this study, liquid phantom simulating the optical
properties of an adult human head was used.
[0116] The basis of the phantom is formed by a scattering solution
of Intralipid and phosphate buffered saline with pH=7.4. Certain
concentration of Intralipid and water is mixed until a typical
overall reduced scattering coefficient of brain is reached. The
solution is placed in the brain layer of the liquid head phantom
which is a cubic container of approximately 10 cm on each side with
a magnetic rod that stirred the solution during the course of the
experiments. Red blood cells obtained from healthy sheep blood was
added to the intralipid solution that contained no hemoglobin at
the start of the experiment to achieve a volume fraction of 1.5%
and total hemoglobin concentration of 26 .mu.M. This is a typical
value for normal physiological conditions with an assumption of 4%
blood volume and 40% hematocrit. The hemoglobin saturation in the
added red blood cells was adjusted to .about.90%. In order to
change oxygen saturation and to induce deoxygenation, baker's yeast
was added to the solution obtained as explained above. The
temperature of the phantom was maintained at 37.degree. C. to keep
the yeast active. This condition is maintained over the time course
until deoxygenation of yeast-intralipid solution reaches steady
state. Then oxygenation is induced again by delivering extra oxygen
to the liquid phantom from an oxygen tank. Oxygen supply is
maintained until a steady state level of oxygenation is
obtained.
[0117] (Experiment I) Edema development under different Oxygen
Saturation conditions: When edema develops after brain injury or a
hypoxic event, swelling in the brain can cause elevation of
intracranial pressure and reduction of cerebral blood flow which
can further change the blood oxygenation and cause further hypoxia
or ischemia. Regardless of such a situation, since measurements
will be obtained from the frontal cortex, any brain activity can
cause changes in HbO.sub.2 and Hb levels which can in turn affect
signal levels. Hence, changes in blood content should be extracted
and closely monitored together with the water content for the
reliable and robust monitoring of edema.
[0118] In this experiment, the water content through diffuse and
focal edema models in the presence of changes in the blood
oxygenation was changed. The algorithms and the parameters used in
the algorithms are adjusted to provide more reliable and robust
measurements. In these experiments, the performance of the
prototype edema monitoring system 110 with a thin strip NIR sensor
112 composed of light sources at 730, 850 and 940/960 nm
wavelengths and the data acquisition box 114 was evaluated. The
device and the analysis methods based on MBLL are tested in the
separation of blood and water content under different blood
oxygenation conditions.
[0119] Diffuse Edema Tests: In these experiments the oxygenation of
intralipid+blood+water solution in the brain layer of the phantom
is first adjusted to .about.90% saturation and then yeast is added
to induce deoxygenation. Once deoxygenation reached steady state
around .about.10% blood oxygenation is increased once more by
introducing oxygen to the solution until saturation reached steady
state at .about.90%. Diffuse edema model is simulated by adding a
certain percentage of water (10%) to the brain layer solution at
different blood oxygenation conditions (.about.90%, .about.50% and
.about.10% oxygen saturation).
[0120] In FIG. 20, the results of MBLL providing relative changes
in water, Hb and HbO.sub.2 concentrations according to the first 10
second recording at the start of the experiment using the raw
intensity measurements at 730, 850 and 960 nm wavelengths of the
NIR device are shown. During the course of the experiment 10% water
is added to the base solution at .about.90%, .about.50% and
.about.10% oxygen saturation conditions. Each time after the water
is added to the solution, the concentration of water increases and
concentrations of Hb, HbO.sub.2 and Hbt (blood volume or total
hemoglobin Hbt=Hb+HbO.sub.2) decreases since they become diluted.
When the yeast is added to the solution it induces deoxygenation
and hence Hb increases while HbO.sub.2 decreases. During this
process Hbt and water concentrations remain relatively constant as
expected. The water, Hb and HbO.sub.2 concentration changes as
measured by with 730, 850 and 940/960 nm wavelengths completely
followed expected patterns in this experiment.
[0121] Focal Edema Tests: In these experiments, the same procedure
is applied to induce oxygenation and deoxygenation as in the
diffuse edema model tests. Here focal edema is simulated by
inserting a rubber balloon filled with water to mimic edema of size
20 cc in the intralipid+blood+water solution in the brain layer of
the phantom as shown in FIG. 21.
[0122] Results of MBLL as the relative changes in water, Hb,
HbO.sub.2 and Hbt concentrations using the prototype edema
monitoring device measurements are shown in FIG. 22. In this
experiment, 20 cc volume focal edema was inserted and taken out at
.about.90%, .about.50% and .about.10% oxygen saturation
conditions.
[0123] In these focal edema experiments, when the focal edema model
is inserted within the brain layer independent of the oxygen
saturation the measured water concentration increases, as expected.
Since the blood concentration becomes diluted, Hb, HbO.sub.2 and
Hbt decrease during the focal edema condition. These expected
results are captured with the edema monitoring device with the use
of the light source at 960 nm wavelength (a 940 nm light source may
also be used).
[0124] The focal and diffuse edema tests were repeated several
times. The same results were obtained in the repeated trials when
the change in water content (edema size) is kept the same. When
change in water content is increased from focal edema of 10 ml (see
FIG. 23) to 30 ml (see FIG. 24), the measurements obtained by the
proposed edema monitoring device reflect the change successfully
and repeatedly. In the case of 10 ml focal edema change, water
content was .about.1.mu.mol, where as in the case of 30 ml focal
edema, it was .about.2.5 .mu.mol.
[0125] (Experiment II) Hematoma tests under different Oxygenation
Saturation conditions: After traumatic brain injury, edema and
hematoma can develop separately or together at the same time or one
after the other. In this experiment, the development of hematoma
without the presence of edema was modeled and the performance of
the prototype device and the analysis techniques in the separation
of blood and water content was tested. Here, hematoma is simulated
by inserting a rubber balloon filled with 20 cc volume of red blood
cells using a stable holder in an intralipid+blood+water solution
in the brain layer of the phantom similar to the focal edema
model.
[0126] FIG. 25 shows the relative changes in water, Hb, HbO.sub.2
and Hbt concentration for 20 cc hematoma test obtained. As in focal
edema experiments, the hematoma model is inserted during
.about.90%, .about.50% and .about.10% oxygen saturation conditions.
In all of the blood oxygenation conditions, Hbt concentration
increases with the insertion of the hematoma as expected. Change in
Hb and HbO.sub.2 depends on the oxygen saturation of the blood
within the balloon and within the brain layer solution outside the
balloon. The water content was expected to drop a little bit as was
the case in most of the oxygen saturation conditions.
Example 3
Human Testing
[0127] A study was performed with severe head trauma patients of
ages between 18-65 admitted to an intensive care unit (ICU) and
confirmed with edema development through computed tomography (CT)
scanning. The NIR sensor is attached on the patient's forehead with
a hypoallergenic medical grade adhesive tape. Measurements from the
NIR sensor attached to the patients' frontal scalp are taken
serially for 10-20 minutes every 6 hours for a total of 72 hours
period following the onset of first measurement. The sensor was not
removed until all the measurements are collected within the 72
hours period following the initial measurement in order to avoid
the possibility of placing the sensor on a different location on
the forehead with different optical properties. The sensor remained
attached but is powered off when it is not recording in order to
eliminate unnecessary application of light and heating to the
forehead. Serial data collection over a period of time is necessary
in order to be able to monitor possible changes in edema
development. In addition to NIR measurements, patients'
neurological status obtained through Glasgow coma scale (GCS)
scores, intracranial pressure monitoring (ICP) and CT or magnetic
resonance imaging (MRI) scans were also obtained serially for
correlation analysis to validate the efficacy of NIR technology in
edema monitoring. A thin strip NIR sensor with light sources at
730, 850 and 960 nm wavelength was used.
[0128] Patient 1: A first patient was a 48 year old white male who
had two gunshot wounds to the head. The edema monitoring device
used in this study was composed of: i) a thin strip sensor housing
LED type near infrared (NIR) light sources at three wavelengths at
730, 850 and 960 nm and light detectors; ii) a data acquisition box
to power the light sources and to collect data from the light
detectors; and iii) a laptop computer for data collection and
storage.
[0129] The edema monitoring sensor was placed on the patient's
forehead with a cushioning material for comfort and a
hypoallergenic medical grade adhesive tape to hold the sensor in
place during the course of data collection. Data collection
recorded measurements from the edema monitoring sensor at 2 Hz from
the contra-lateral sides of the forehead at depth .about.2 cm
serially for 20 minutes every 6 hours in 3 days period following
the onset of first measurement by automatically turning the device
on and off. Once the data from the edema monitoring device was
finalized, the sensor was detached. Other neurological and
physiological measurements such as Glasgow coma scale (GCS) scores,
intracranial pressure (ICP) monitoring recordings and computed
tomography (CT) scan results recorded at the same day and time
points on the patient were obtained for performance evaluation of
the device.
[0130] Average of raw intensity measurements at 730, 850 and 960 nm
wavelengths at 3 cm source detector separation on the right side of
the head during 12 consecutive measurements collected every 6 hours
from Patient 1 is shown in FIG. 26. For the same subject and
conditions, the change in oxygenated (HbO.sub.2) and deoxygenated
hemoglobin (Hb) and water content extracted using MBLL is presented
in FIG. 27. Here only the right side measurements are used because
proper placement of the sensor on the left side was not possible.
On the 3rd and 11th recordings, the recordings were either
saturated or too noisy which may be because of a loss of coupling
of the sensor with the skin.
[0131] From the patient log, it was found that around the time the
first recordings was obtained, patient had facial edema, on the
2nd, 3rd and 4th recordings CSF drainage was performed, and on the
6th recording eye edema was observed. The patient had an overall
GCS score of 3 during the corresponding 3 days of data collection.
During this time ICP recordings got higher during the 6th and 7th
recordings as compared to the previous recordings which lowered
gradually until 12th recording. This change in intracranial
pressure was also reflected in both the raw intensity measurements
(FIG. 26) and also in blood and water level changes (FIG. 27).
[0132] Further analysis was performed separately on the
correlations of ICP and cerebral perfusion pressure (CPP) with
HbO.sub.2, Hb and water content. The correlation results are
summarized in Table 1. In FIGS. 28 and 29, edema device recordings
vs ICP and CPP values for Patient 1 at different recording sessions
are shown. High correlation values were observed between the edema
monitoring device recordings and physiological parameters (ICP and
CPP), especially for this patient where there was a lot of change
observed in ICP (from 7 to 25) and CPP values. Since GCS scores
remained unchanged during the course of the recordings, no further
correlational analysis on GCS and edema device recordings was
performed.
TABLE-US-00001 TABLE 1 Correlation coefficient (R) between ICP and
CPP values and various edema monitoring measurements for Patient 1
(right side recording) HbO.sub.2 Hb Water ICP R = -0.74 R = -0.77 R
= 0.74 CPP R = 0.78 R = 0.75 R = -0.65
[0133] Patient 2: The second patient was a 65 year old white male
who was in a motorcycle accident when driving without a helmet. The
main injury site on this patient was on the right side of the brain
where edema and hematoma were developed and removed through
neurosurgery. The sensor was secured on the patient's forehead with
adhesive tape and 20 minutes of data was collected every 6 hours
within the 72 hour period after the start of the data collection
protocol at 2 Hz from contralateral sides of the brain.
Neurological and physiological measurements including GCS scores
and ICP and CPP values were recorded at the same day and time
points with the edema monitoring recordings.
[0134] For this patient, injury was on the right side of the head.
Moreover, there were bruises on the skin of the right forehead
which caused the signal levels to be too low and not reliable on
this side. The average of raw intensity measurements at 730, 850
and 960 nm wavelengths at 3 cm source detector separation on the
left side of the head is shown in FIG. 30. The change in HbO.sub.2,
Hb and water content is shown in FIG. 31. Over the 12 recordings
(every 6 hours within 3 days period), the noisy or saturated
recordings or when the ICP bolt is taken out (after 9th recording)
are not shown in FIGS. 30 and 31. The GCS scores for this patient
during the recording period was 10, patient was opening his eyes
time to time, moving his arms and legs, but not following commands
most of the time. After the 9th recording, the patient's condition
was mostly stabilized and the ICP bolt was taken out. During the
whole recording period the ICP values were mostly very low.
[0135] A correlational analysis between ICP and CPP values with
HbO.sub.2, Hb and water content as measured by the edema monitoring
device was performed and is summarized in Table 2. In FIGS. 32 and
33, edema device recordings in terms of HbO.sub.2, Hb and water
content vs ICP and CPP values at different recording sessions are
shown. Since the patient was mostly stabilized during the whole
recording session, there was not much change in the ICP values
(mainly around 7-9) and some change was observed in CPP, therefore
correlation with edema monitoring device recordings was found to be
moderate with CPP values.
TABLE-US-00002 TABLE 2 Correlation coefficient (R) between ICP and
CPP values and various edema monitoring measurements for Patient 2
(left side recording) HbO2 Hb Water ICP R = -0.21 R = 0.12 R = 0.31
CPP R = 0.40 R = 0.73 R = -0.40
Example 3
Animal (Piglet) Testing
[0136] For purposes of further testing the NIR based brain
monitoring system having three wavelength light sources and signal
processing algorithms, the development of cerebral edema following
hypoxia was monitored and an assessment of cerebral autoregulation
in a piglet study was performed.
[0137] Edema Monitoring: After obtaining relevant IACUC approval,
newborn piglets were exposed to hypoxia (HI) [FiO.sub.2 0.07 for 1
hr and hypotension (40% decrease in systolic BP)], then returned to
FiO.sub.2 0.21 to restore O.sub.2 and BP for 4 hrs (HI-4Hr; n=2),
Anesthesia was induced with 4% Isoflurane and maintained with 79%
nitrous oxide, fentanyl analgesia and vecuronium paralysis.
Normoxic piglets (Nx-4Hr; n=2) were ventilated with FiO.sub.2 0.21.
One of the NIR based split sensors was placed on the piglet head
(the other one is placed on the back of the piglet), and recordings
were made at 3 different wavelengths (730 m 850 and 940 nm) to
couple changes in light attenuation to changes in deoxyHb, oxyHb
and water, respectively. The height of the cerebrospinal fluid
column was recorded at the end of the recording, with
values.gtoreq.11 cm H.sub.2O representing an elevated ICP based on
reported human infant data. Cerebral water content (ml water/gram
tissue) was determined as wet-dry weights/wet weight of samples of
the cerebral cortex measured before and after incubation for 72 hrs
at 90.degree. C. Results are expressed as M+SEM.
[0138] FIG. 34 shows a representative tracing obtained from one HI
and one Nx piglet. DeoxyHb signal increased and oxyHb signals
decreased predictably with the onset of and during hypoxia, and
returned to baseline after reoxygenation. Arterial blood gas values
during the period confirmed hypoxemic PaO.sub.2 values. Water
signal increased progressively from baseline following the
hypoxia-ischemia period, indicating cerebral edema. NIRS-derived
cerebral water signal (units) was 25.88.+-.3.77 in HI-4Hr (n=6) and
5.42.+-.4.48 in Nx-4HR (n=5) piglets. Overall, all HI piglets and
none of the Nx piglets had elevated ICP at 4 hours pose HI
(12.7.+-.1.86 vs 9.5.+-.1.0 cm H.sub.2O). Cerebral water content
(ml water/gram tissue) was 5.83.+-.0.11 in HI and 5.45.+-.0.29 in
Nx-4Hr piglets. The data shows that the increase in NIRS-derived
cerebral water signal correlated well with increases in both
cerebral water content and intracranial pressure (see FIGS. 35, 36
and 37).
[0139] Significant correlations between NIRS-derived cerebral water
signal and the ICP measurements (R=0.75, p<0.05) and the
cerebral water content (R=0.74, p<0.01) were also found as shown
in FIG. 41. These results suggested that NIRS derived water signal
values can reflect the change in the amount of cerebral water
content and the increased ICP related with it.
[0140] Cerebral Autoregulation Assessment: In the experiment
explained above during the length of the recording at certain time
intervals, a combination of anesthetic agents and saline was
injected intravenously. Following the injection of the medication
combination, a certain type of signal change (a gamma type signal
reduction in values) in all the NIRS recordings (Hb, HbO.sub.2 and
water content) is observed for a period of .about.2 min. As an
example, averaged signal epochs for a Hypoxic and a Normoxic piglet
are shown in FIGS. 38 and 39.
[0141] It was expected that more reduction in the signal following
drug injection will be observed in hypoxic piglets as compared to
the normoxia cases due to the change in the cerebral autoregulation
of piglets that are exposed to hypoxia. For purposes of testing
this hypothesis, 2 minute data epochs were extracted directly after
each medication and saline injection on the recordings obtained
from the head. Each epoch is baseline corrected using 1 second of
data prior to injection (mean of the pre-injection is subtracted
from the epoch). For the comparison of the dip in Nx and HI cases,
the minimum value within the first 1 minute of the epoch for each
chromophore, Hb, HbO.sub.2 and water was extracted.
[0142] The minimum dip values in Nx and HI piglets for all the
chromophores are summarized in Table 3. As hypothesized, the HI
piglets resulted in more reduction in all of the chromophores (Hb,
HbO.sub.2 and water where water provided the most prominent change)
following saline and drug injection as compared to Nx piglets due
to differences in cerebral autoregulation following a hypoxic event
(FIG. 40). These results suggest that the proposed NIR based brain
monitoring device with its capabilities in monitoring of Hb,
HbO.sub.2 and water content changes can be used in the assessment
of cerebral autoregulation. This capability provides clinicians
with very important information on the existence/absence of a prior
hypoxic event. By injecting saline and medication to the patient
which is already a common procedure in clinically ill infants,
clinicians can monitor changes in the signals as measured by the
proposed device for a short period of time (.about.2 min) and
decide if a hypoxic event has happened before or not, or when did
it happen or they can also monitor treatment outcomes not only for
reduction or edema development, but also, in returning back to
normal cerebral autoregulation levels.
TABLE-US-00003 TABLE 3 Averaged minimum values in Hb, HbO2 and
water after medication injection for Nx and HI piglets Hb HbO2
Water Nx -1.15 .+-. 0.41 -1.35 .+-. 0.60 -1.92 .+-. 0.98 HI -2.28
.+-. 0.71 -2.28 .+-. 1.56 -4.63 .+-. 1.58
[0143] Early detection and rapid treatment of brain edema is
critical to prevent development of severe brain injury. The
embodiments disclosed above provide a non-invasive testing device
for use by clinicians to detect and monitor the progress of brain
edema. In addition, embodiments disclosed above provide information
on cerebral autoregulation that can guide certain therapies in case
of a prior hypoxic event. The hand-held non-invasive device for the
monitoring of brain edema and cerebral autoregulation according to
embodiments disclosed herein significantly enhance and aid current
clinical practices/treatments by: i) providing accurate and
immediate clinical decision support as allowing to triage patients
with edema; ii) allowing frequent monitoring of the progress of
brain edema and a reduction of unnecessary invasive surgeries; and
iii) measuring cerebral autoregulation to provide information on
the existence of prior hypoxic event to guide in therapeutic
interventions.
[0144] Accordingly, embodiments of the NIR based brain monitoring
device disclosed herein use three light sources at 730 nm, 850 nm
and 940 nm (or 960 nm) wavelengths to monitor changes in Hb,
HbO.sub.2 and water content in the brain and includes a thermistor
to monitor temperature changes. The device utilizes additional
signal analysis components to adjust parameters (molar extinction
coefficients and DPF values) in the MBLL algorithm for changes
related to wavelength, source-detector separation, temperature and
oxygen saturation and also for head movement or laying position
related artifacts. Methods are provided for the detection and
monitoring of cerebral edema and for the assessment of cerebral
autoregulation.
[0145] While the principles of the invention have been described
above in connection with specific devices, systems, and/or methods,
it is to be clearly understood that this description is made only
by way of example and not as limitation. One of ordinary skill in
the art will appreciate that various modifications and changes can
be made without departing from the scope of the claims below.
Accordingly, the specification and figures are to be regarded in an
illustrative rather than a restrictive sense, and all such
modifications are intended to be included within the scope of the
present invention.
* * * * *